1. Field of the Invention
This invention is in the general field of pharmacology, and relates in particular to oral dosage formulations that deliver drugs by controlled release in the stomach for a prolonged period of time.
2. Description of the Prior Art
Many drugs have their greatest therapeutic effect when released in the stomach, particularly when the release is prolonged in a continuous, controlled manner. Drugs delivered in this manner cause less side effects and provide their therapeutic effects without the need for repeated dosages, or with a low dosage frequency. Localization of the drug delivery in the stomach is an advantage for the treatment of local disorders of the stomach such as esophageal reflux disease, for the eradication of ulcer-causing bacteria in the gastric mucosa, and for the treatment of disorders that require sustained antacid action. Sustained release in the stomach is also useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, which is where absorption occurs and contact time is limited. Under normal or average conditions, for example, material passes through the small intestine in as little as 1 to 3 hours. For drugs that are absorbed almost exclusively in the small intestine, such as captopril and the cephalosporins, this short contact time limits the bioavailability of these drugs, particularly when the drugs are administered in a controlled-release dosage form.
The passage of matter through the stomach can be delayed in the normal digestive process by the physiological condition that is variously referred to as the digestive mode, the postprandial mode, or the “fed mode” (the latter term is used in the remainder of this specification for convenience). When the stomach is not in this mode, it is in the interdigestive or “fasting” mode. The difference between the two modes lies in the pattern of gastroduodenal motor activity.
In the fasting mode, the stomach exhibits a cyclic activity called the interdigestive migrating motor complex (IMMC). This activity occurs in four phases:                In Phase I, which lasts 45 to 60 minutes and is the most quiescent, few or no contractions occur.        In Phase II, irregular intermittent sweeping contractions occur that gradually increase in magnitude.        In Phase III, intense bursts of peristaltic waves appear in both the stomach and the small bowel. This lasts for 5 to 15 minutes.        Phase IV is a transition period of decreasing activity which lasts until the next cycle begins.        
The total cycle time is approximately 90 minutes, and the contents of the stomach are swept out by the powerful peristaltic waves that occur during Phase III. Phase III of the IMMC thus functions as an intestinal housekeeper, sweeping swallowed saliva, gastric secretions, food particles, and particulate debris to the small intestine and colon, and preparing the upper tract for the next meal while preventing bacterial overgrowth. Pancreatic exocrine secretion of pancreatic peptide and motilin also cycle in synchrony with the motor pattern.
The fed mode is induced by nutritive elements immediately after food ingestion, and begins with a rapid and profound change in the motor pattern of the upper gastrointestinal GI tract, the change occurring over a period of 30 seconds to one minute. The change occurs almost simultaneously at all sites of the GI tract, before the stomach contents have reached the distal small intestine. Once the fed mode is established, the stomach generates 3-4 continuous and regular contractions per minute, similar to those of the fasting mode but of about half the amplitude. The pylorus is partially open, causing a sieving effect in which liquids and small particles flow continuously from the stomach into the intestine while indigestible particles greater in size than the pyloric opening are retropelled and retained in the stomach. This sieving effect thus causes the stomach to retain particles exceeding about 1 cm in size for approximately 4 to 6 hours.
The minimum particle size that will be retained in the stomach is thus substantially smaller in the fed mode than in the fasting mode. Particles large enough to be retained in the fasting mode are too large for practical administration in most patients. Particles of a smaller particle size can be retained in the stomach if they are administered to a patient who is in the fed mode, and this serves as an effective and feasible means of prolonging the residence time of these particles in the stomach.
While onset of the fed mode is normally caused by the ingestion of a meal, the use of a meal as a means of prolonging the residence time of a drug in the stomach has certain disadvantages. One disadvantage is a lack of reliability, since although a variety of nutritive elements are capable of inducing the fed mode, different individuals consume meals of different compositions, some inducing the fed mode more easily and for different durations than others. Another disadvantage is that many drugs are adversely affected by the presence of food in the stomach. Thus, a meal-induced fed mode can increase the absorption of some drugs, while decreasing the absorption of others. These disadvantages are avoided by inducing the fed mode through means other than the ingestion of a meal.
While the fed mode promotes the retention of relatively small particles in the stomach, there are still many patients for whom even these particles are too large to be comfortably ingested. For these patients, particles that are initially small enough for comfortable ingestion and swell to a larger size upon contact with the gastric fluid in the stomach can be used. The swelling can occur as a result of hydration of the particle material upon absorption of water from the gastric fluid. Alternatively, the swelling can occur as a result of gas generation, such as carbon dioxide for example, by contact of gastric fluid with the dosage form, the gas generation occurring in a membrane bag or otherwise within the dosage form. A still further alternative is the use of a large tablet held in a compressed condition by mechanical tension within a small capsule and released to expand to its full relaxed size when the capsule contacts gastric fluid. Whether the particles are large enough for fed mode retention before they are ingested or reach that size by swelling or expansion in the stomach, it is important that the particles retain their size while the drug is released into the gastric fluid. Thus, release of the drug must not itself cause the particle to shrink below the minimum size required for retention in the fed mode. Also, the quantity of drug in the formulation should be controllable independently of the particle size. Thus, while the particles must be large enough to be retained in the stomach and contain enough inert carrier to maintain their size during drug release, there should be no need for the patient to ingest a large number of particles to achieve the needed drug dose.
The need for administering and maintaining particles of appropriate size has been addressed by U.S. Pat. No. 5,007,790 (“Sustained Release Oral Drug Dosage form,” Shell, inventor, Apr. 16, 1991). This patent discloses particle-form oral drug delivery systems in which the particles are small when taken orally but swell in the gastric fluid to a diameter of approximately 8 to 11 mm. Swelling to this size requires approximately two hours. Retention of the particles in the stomach while they are swelling requires that the patient be in the fed mode when the drug is administered, or at least that the swelling occur before the Phase III IMMC waves of the fasting mode begin. With control of the IMMC waves dependent on the timing of the fed mode and the manner in which the fed mode is induced, the particle size and retention are subject to uncertainty, and the duration of the retention is at times, and in some individuals, less than desired.
Induction of the fed mode by pharmacological means is reported in the literature, particularly by J. N. Hunt and his co-workers (J. Physiol. 201:327(1968)). The most potent pharmacological agents reported for this purpose are straight-chain fatty acids with optimal activity at a chain length in the vicinity of 12 carbons. Use of these agents for maintaining the fed mode for a period of hours in dogs or humans, however, requires dosages in the range of 0.5 g to 1 g. Other agents that have been reported to induce the fed mode are glucose and tryptophan, but these require even higher dosages. John Stephens and co-workers (Am. J Physiol. (1976) 231:848-853 and Gastroenterol. (1975) 69:920-927) reported that amino acids such as glycine, arginine and tryptophan slowed gastric emptying in dogs when administered in excess of 1 g similar to results obtained for glucose. The literature reports that all of these agents, with the exception of tryptophan, slow gastric emptying by their osmolarity and consequently fail to suggest any potent specific agents. The low potency of these reported agents makes it difficult to incorporate them in effective amounts in a sustained-release oral dosage form such as a capsule or tablet since the capsule or tablet must be small enough for ingestion and yet contain effective amounts of the agent, the drug, and any excipients needed for controlling the release of the drug.
R. Groning and G. Heun (Drug Dev. Ind. Pharm. 10:527 (1984) and Int. J. Pharmaceut. 56:111 (1989)) incorporated salts of myristic acid (the 14-carbon fatty acid) into a double capsule or two-layer immediate release dosage form containing either riboflavin or nitrofurantoin as active drugs. These salts are not of high potency, however, and the amounts administered, 107.5-165 mg per dosage form, had only a marginal effect on gastric retention, increasing the retention time by only about 1 to 2 hours. An agent that can be incorporated into a dosage form at a low dose and yet achieve a mean gastric retention time of 4-6 hours similar to food has not been reported.